Vulnerability to initiate and relapse to cocaine use varies among individuals due to both genetic and environmental factors. Acquisition of IV cocaine self-administration is enhanced in male Lewis vs. Fischer (F344) inbred rats and in adult male outbred rats with neonatal isolation experience. These effects may reflect, in part, differences in the corticotrophin releasing factor (CRF)-hypothalamic-pituitary-adrenal CHPA) axis system, a system involved in the interactions of stress and cocaine. CRF-HPA axis function is altered by early life stress which is thought to reflect differential maternal behavior received post-stress. Lewis and F344 rats differ in CRF-HPA axis function that may relate to reported strain differences in maternal behavior. Maternal behavior also differs by sex of the pup that may be a link to the sex differences in behavioral and HPA axis responses to stress and cocaine. We hypothesize that organizational effects on this system occur during early post-natal development due to differential mother-pup interactions leading to altered behavioral and CRF-HPA axis responses to stress and cocaine in adult male and female rats. Such environmental manipulations may mitigate the role of strain and sex on these responses and this would have major implications for prevention of drug addiction. This hypothesis will be tested in a transdisciplinary manner through a coordinated series of studies using behavioral and molecular procedures. Behavioral assessments include acquisition and drug- and footshock-induced reinstatement of cocaine selfadministration responding, and locomotor, affective, and discriminative stimulus effects of cocaine. Molecular assessments of pituitary and brain CRF, CRF1, POMC, and Type I and II glucocorticoid receptor mRNA levels as well as plasma concentrations of corticosterone and adrenocorticotrophin levels will be made. After characterizing the effects of neonatal isolation on mother-pup interactions and CRF-HPA axis function in Lewis and F344 rats in Specific Aim 1, the behavioral and molecular responses to cocaine and footshock stress will be examined after manipulations of mother-pup interactions in Specific Aims 2 and 3, using neonatal isolation and cross-fostering. Data obtained will illuminate how early life stress, genotype, and gender interact to promote initiation and relapse to cocaine abuse.